PROJECT SUMMARY/ABSTRACT The following proposal is submitted by Dr. Jason Roh, MD, MHS, in response to RFA-AG-19-017. Dr. Roh is a cardiologist at Massachusetts General Hospital (MGH) and Instructor at Harvard Medical School (HMS). With a combined interest in geriatrics, cardiology, and aging biology, he established the first geriatric-cardiology clinic at MGH and has been investigating the role of aging in heart failure (HF). He is currently funded by an American Heart Association Fellow-to-Faculty Award to study Activin type II receptor (ActRII) signaling in HF and was recently recognized with American College of Cardiology and Northwestern Cardiovascular Young Investigator?s Awards. Based on his prior research, Dr. Roh is proposing an innovative study with promising translational potential that will focus on ActRII signaling in age-related frailty and HF. This proposal is based on his preliminary data suggesting that catabolic ActRII signaling is altered by aging and directly contributes to HF pathobiology. A strong association between advanced age, frailty, and cardiovascular disease (CVD) is well- established. However, whether common biological mechanisms drive these age-related pathologies ? and importantly whether they can be effectively intervened upon ? remain unclear. Here, Dr. Roh proposes a 4- year program of career development and mentored research to achieve his long-term career goals of 1) becoming a leading expert in aging biology in CVD and 2) developing novel therapies for heart disease in older adults. Within the highly productive and supportive environment of the MGH Cardiovascular Research Center and the HMS aging research community, he will work with his mentors, Drs. Anthony Rosenzweig, Lewis Lipsitz, Jennifer Ho, and Dae Kim, on this integrated study spanning aging, frailty, and HF biology. The overarching hypothesis is that increased ActRII signaling is causal in both frailty and HF pathobiology in older adults, and that targeted ActRII inhibition can be used as a therapeutic strategy. The significance of this work is highlighted by two major points: 1) HF is the leading cause of hospitalization amongst older adults, and 2) there are currently no therapies that improve mortality in heart failure with preserved ejection fraction (HFpEF), the leading cause of HF in older adults. Notably, the translational potential of this work is underscored by ongoing clinical development of ActRII inhibitors for other indications (e.g. muscular dystrophy), which could enable rapid translation of his findings. To achieve his goals, Dr. Roh will accomplish the following 3 specific aims. Aim 1 is designed to determine if ActRII activity correlates with cardiac and frailty phenotypes and health outcomes in older HF patients. Aim 2 expands on these findings in animal models to determine if ActRII signaling is causal in age-related frailty and HFpEF. Lastly Aim 3, will use state-of-the-art single cell RNA sequencing and molecular biology techniques to elucidate mechanisms by which ActRII signaling modulates function in the aging heart and skeletal muscle. Completion of the proposed career development plan will position Dr. Roh to successfully compete for NIA R01 funding and become a leader in cardiovascular aging.